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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4090-4097
 c Gene Transfer in the Presence of Stem Cell Factor, FLT-3L,
Interleukin-7 (IL-7), IL-1 , and IL-15 Cytokines Restores T-Cell
Differentiation From c( ) X-Linked Severe Combined
Immunodeficiency Hematopoietic Progenitor Cells in Murine Fetal
Thymic Organ Cultures
S. Hacein-Bey,
G. De Saint Basile,
J. Lemerle,
A. Fischer, and
M. Cavazzana-Calvo
From the Institut National de la santé et de la Recherche
Médicale U429 et Centre de Transfusion Sanguine, Hôpital
Necker-Enfants Malades, Paris Cedex, France.
X-linked severe combined immunodeficiency (SCID-Xl) is a rare human
inherited disorder in which early T and natural killer (NK) lymphocyte development is blocked. The genetic disorder results from mutations in the common  c chain that participates in several cytokine receptors including the interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. We have shown in a previous report that c
gene transfer into SCID-Xl bone marrow (BM) cells restores efficient NK
cell differentiation. In this study, we have focused on the
introduction of the c gene into SCID-Xl hematopoietic stem cells
with the goal of obtaining differentiation into mature T cells. For
this purpose, we used the in vitro hybrid fetal thymic organ culture
(FTOC) system in which a combination of cytokines consisting of stem
cell factor (SCF), Flt-3L, IL-7, IL-1 , and IL-15 is added
concomitantly. In this culture system, CD34+ marrow cells
from two SCID-Xl patients were able to mature into double positive
CD4+ CD8+ cells and to a lesser degree into
CD4+ TCR + single positive cells after
retroviral-mediated c gene transfer. In addition, examination of the
output cell population at the TCR DJ1 locus exhibited multiple
rearrangements. These results indicate that restoration of the
c/JAK/STAT signaling pathway during the early developmental stages
of thymocytes can correct the T-cell differentiation block in SCID-Xl
hematopoietic progenitor cells and therefore establishes a basis for
further clinical c gene transfer studies.
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